Ventricular arrhythmias remain the single most important cause of sudden cardiac death (SCD) among adults living in industrialized nations. Genetic factors have substantial effects in determining population-based risk for SCD and may also account for interindividual variability in susceptibility. Great progress has been made in identifying genes underlying various Mendelian disorders associated with inherited arrhythmia susceptibility. The most well studied familial arrhythmia syndrome is the congenital long QT syndrome (LQTS) caused by mutations in genes encoding subunits of myocardial ion channels. Not all mutation carriers have equal risk for experiencing the clinical manifestations of the disease (ie: syncope, sudden death). This observation has raised the possibility that genetic factors other than the primary disease-associated mutation can modify the risk of LQTS manifestations. This proposal outlines an international collaboration designed to investigate the role of candidate modifier genes in determining disease expression in a unique founder population of 17 LQTS families in South Africa. We hypothesize the existence of two types of modifier genes: genes which affect the magnitude of the underlying myocardial arrhythmia substrate, and genes which affect the propensity for triggering events acting through the autonomic nervous system. The primary goals of the study include further ascertainment and extension of the identified pedigrees and to assess a variety of surrogate clinical markers of autonomic function in mutation carriers (Specific Aim 1), to examine multiple candidate modifier genes for their association with symptomatic and asymptomatic disease (Specific Aim 2), and to test the hypothesis that variable transcriptional control of the primary disease gene (KCNQ1) impacts on arrhythmia susceptibility (Specific Aim 3). Identification of LQTS modifiers will enhance our understanding of the pathophysiology of LQTS, provide new and valuable information for counseling patients with this disorder, and will contribute to our understanding of more common arrhythmia syndromes associated with highly prevalent cardiac diseases (e.g. ischemic heart disease and congestive heart failure) that are burdened by a high incidence of SCD.